1. Field of the Invention
The invention relates to novel nitroprussides of short-acting ganglionic agents, particularly to the novel compound bis-(trimethaphan)-nitroprusside and its (+)-isomer of formula ##STR1## and solvates, especially hydrates or alcoholates thereof, as well as a process for the manufacture thereof from an alkali nitroprusside and a soluble trimethaphan salt, especially sodium nitroprusside and trimethaphan camsylate, in solution, especially in water.
The invention also relates to mixtures of an alkali metal nitroprusside, such as sodium nitroprusside, and a soluble salt of a short acting ganglionic blocking agent, such as a soluble trimethaphan salt, particularly of (+)-trimethaphan. Trimethaphan camsylate or halogenide, such as the chloride or bromide, are also suitable.
The invention further relates to concentrated solutions (stock solutions) containing said novel nitroprussides and mixtures.
Furthermore, the invention relates to pharmaceutical compositions which contain said novel nitroprussides and mixtures in solid form, in form of concentrated solutions or in form of diluted solutions suitable for infusion purposes.
Preferred mixtures described are those containing the nitroprusside and the salt of a short acting ganglionic blocking agent, especially of trimethaphan or its (+)-isomer, in the weight ratio of 1:&lt;10, especially in a ratio representing the nitroprusside salt of the ganglionic blocking agent, e.g., bis-(trimethaphan)-nitroprusside. Also described are solutions, especially concentrated (stock) solutions of said nitroprussides and mixtures in physiologically acceptable alcohols, especially in aqueous ethanol.
Also described are said nitroprussides, especially bis-(trimethaphan)-nitroprusside, as well as its solvates, and said mixtures, especially those of an alkali nitroprusside and a soluble trimethaphan salt, preferably in the weight ratio of less than 1:10, especially of about 1:4, when being dissolved in a physiologically acceptable alcohol, especially in aqueous ethanol, especially at least 40% or preferably about 60% ethanol.
As was noted above, the invention relates to the use of the inventive composition in a weight ratio of less than 1:10, and preferably about 1:4. The invention thus includes the range of 1:4-&lt;10. Within this range, narrower ranges of 1:9, 1:8, 1:7, 1:6, and 1:5 may be listed by way of example. It is clear, of course, that although integers are listed, intermediate ranges are also possible within the range set forth above.
Preferably, these nitroprussides and mixtures are stored in the solid form and dissolved in said alcohol immediately before use. In such a case the alcohol may, in addition, contain other physiologically acceptable alcohols, such as polyols, like glycerol, inositol, pentaerythritol, mannitol or isosorbitol as well as nitrates, like mono-, di-, tri- or tetranitrates, thereof, especially nitroglycerin, preferably in an amount not exceeding the amount of nitroprusside to be dissolved, as well as nucleosides, such as inosine and adenosine, short acting positive inotropic agents, such as dopamine or dobutamine, a physiologically acceptable thiosulfate, such as sodium thiosulfate, or nicotinic acid and/or its biological precursors, like beta-pyridylcarbinol.
The invention further relates to preparation of infusion solutions from the concentrated solutions or mixtures, the preparation of an especially well soluble micronized mixture of (I) and thiosulphate or of the mixture of the salts and thiosulphate, and the use of the concentrate for the preparation of infusion solutions.
The compound (I), its solvates, the mixture of the salts, and the pharmaceutical compositions containing (I) or the mixture of the salts, are suitable for therapeutic use, particularly in the lowering of blood pressure, in the achievement of peripheral vasodilation, in the elmination of arterial spasms and/or in the reduction of myocardial oxygen consumption and of the work load of the heart after heart attack.
2. Description of the Prior Art
Sodium nitroprusside is a known infusion preparation for the rapid and controlled lowering of the blood pressure in the case of operations or hypertensive crises and for reducing the work load of the heart, e.g., in the case of heart attack. However, it has disadvantages which restrict the use of this valuable and extraordinarily well controllable medicament. Thus, it decomposes in the body very rapidly with the formation of up to 5 moles of cyanide per molecule. Since cyanide is an acutely toxic agent which blocks the respiratory chain and paralyses the respiratory center, SNP must be used in order to avoid an accumulation of toxic cyanide concentrations in the blood serum only with the strictest maintenance of prescribed highest dosages and even then only for a short time.
In common with other vasodilators SNP has the disadvantage that the desired rapid and powerful lowering of blood pressure leads very frequently to an activation of the so-called counter-regulation, whereby, in turn, the amount of circulating hormones which increase blood pressure (adrenalin, noradrenalin and angiotensin II) and of renin is greatly increased. This causes, especially in young patients, a strong tendency to increased blood pressure which can be compensated only by successive increase of the dosage of SNP to be infused (tachyphylaxis). If in such cases the administration of SNP is not discontinued, a dangerous increase of the cyanide level in the blood serum can arise very rapidly, even on short-term use of SNP, because of the over-dosage which then occurs. If in this case the tolerance limit of about 0.8 ug of CN/100 ml of blood plasma is exceeded, severe cyanide poisoning and even death can arise (see Anesthesiology 47, 441-448 (1977); Bull. Med. Legale Toxicol. 21, 215-224 (1978); Amer. J. Obstet. Gynecol. 139, 708-711 (1981).
A further disadvantage of SNP is the appearance of the so-called "rebound" hypertension owing to persistent counter-regulation after termination of the SNP infusion. (New England J. Med. 302, 1029-1030 (1980); Anesthesiology 44, 345-348 (1976)). Since this "rebound" hypertension occasionally causes blood pressure levels which lie far above the initial blood pressure, secondary bleedings can occur in newly operated patients and dangerous blood perfusion disorders in the brain owing to oedema formation can occur in predisposed patients.
Since, on the other hand, SNP is at present the most active agent for the controlled lowering of blood pressure, e.g., during operations, attempts have been made to eliminate the mentioned disadvantages.
MacRae has recently proposed (Anaesthesia 36, 312-315 (1981)) to infuse a very dilute solution containing SNP together with the ganglionic blocking agent trimethaphan camsylate (TMC), in the weight ratio 1:10. He reported that thereby the amount of SNP required for the same lowering of the blood pressure was considerably lower.
TMC and its blood pressure-lowering activity are known and TMC is therefore employed therapeutically (in spite of its lower activity) similarly to SNP, i.e., as an infusion preparation for the controlled short-term lowering of blood pressure. However, TMC displays, in turn, a series of side effects which restrict its use.
Thus, in addition to such side effects as tachycardia, mydriasis, cycloplegia, urine retention, xerostomia and constipation, which occur by blockade of the parasympathetic ganglia, nausea or vomiting can arise in sensitive patients and, especially in children and aged patients, allergies can arise owing to histamine liberation.
Moreover, trimethaphan camsylate must not be used alone in the case of operations in the region of the gastrointestinal tract.
The dosage of SNP required for the controlled lowering of blood pressure is on average about 3 ug/kg body weight per minute, that of the TMC about 30 ug/kg or more per minute. Corresponding to this ratio of the pharmacological activities the concentrations of the infusion solutions usually used are thus 0.01 and 0.1%, respectively. According to Table 2 of MacRae (loc. cit.) a ratio of the dose rates of 1:14 and of the total dosage of 1:10 correspond to the relative strengths of the two agents.
According to MacRae, the clinical activities of the single components in dilute infusion solution containing SNP and TMC in the weight ratio of 1:10 appear to be additive or even become potentiated, while the corresponding side-effects (because of their qualitative difference) are relatively diminished. Thus, seeing that ad hoc preparation of the dilute infusion solution containing such a mixture in the clinic is complicated and, because of the errors which are possible in practice, even dangerous, it appeared advantageous to develop appropriate combination products as well as concentrates thereof which are relatively stable and could easily be diluted to infusion strength.
An additional obstacle to the development of a combination product of nitroprusside and trimethapan was the fact that the two single drugs are not compatible in water and purely aqueous solvents in concentrated form [see for example the solubilities given in Example 10]. When preparing an aqueous solution of the mixture either drug had firstly to be diluted to infusion strength, and these solutions could then be mixed shortly before the infusion. Because of the limited storage stability of dilute solutions of TMC and SNP and because of the known extreme light sensitivity of SNP solutions, such a highly diluted combination produce is, in any event, not suitable as a commercial product.
The observation that the hitherto unknown nitroprussides of short-acting ganglionic agents, such as sulfonium and ammonium bases, for example, pentolinium and tetraethylammonium and, especially, trimethaphan, can be isolated in pure form and in high yield and can be processed to a storable pharmaceutical composition was therefore suprising.
It was also unknown and unobvious that these salts can form solvates and concentrated aqueous alcoholic solutions, especially in view of their limited solubility in water.
It was also not obvious that mixtures of an alkali nitroprusside, such as sodium nitroprusside, and a water-soluble salt of such a short-acting ganglionic blocking agent as trimethaphan camsylate or a halogenide, e.g., the chloride or bromide, could be dissolved in aqueous ethanol and that such solutions, in addition, may contain other physiologically acceptable alcohols, such as polyols, like glycerol, inosotol, pentaereythol, mannitol, or isosorbitol as well as nitrates, like mono-, di-, tri- or tetranitrates thereof, especially nitroglycerin, preferably in an amount not exceeding the amount of nitroprusside to be dissolved, as well as nucleosides, such as inosine and adenosine, short-acting positive inotropic agents, such as dopamine or dobutamine, a physiologically acceptable thiosulfate, such as sodium thiosulfate or nicotinic acid and/or its biological precursors, like beta-pyridylcarbinol.